AIDS patients develop cryptococcal meningoencephalitis because they fail to generate an effective immune response that prevents dissemination of Cryptococcus neoformans from the primary site of infection in the lung to the central nervous system. The objective of the research outlined in this proposal is to understand how a deficit of CD4* T cells leads to the establishment of metastatic foci of infection in the brain. The experiments outlined in this proposal are designed to identify protective immune mechanisms, with the ultimate goal of developing immunotherapy for opportunistic infections in AIDS. Preliminary results from this laboratory indicate that both CD4* and CD8* protective T cells ar induced by a pulmonary infection with an avirulent (opportunistic) strain of Cryptococcus neoformans. However, whereas CD8* T cells are important in the expression of the intrapulmonary immune response, CD4* T cell-dependent immune mechanisms appear to function in systemic responses that prevent the dissemination of the yeast and its establishment in metastatic foci in the brain. The first two aims of this proposal will determine whether protective CD4* T cells are functioning in cell-mediated immunity (CMI), are providing help for the production of protective antibodies, or both. This will be accomplished by documenting the ability of CD4* T cells alone, or in combination with B cells, to reconstitute resistance to Cryptococcus in severe combined immunodeficient (SCID) mice. With the use of neutralizing monoclonal antibodies to IFN-g, a TH1 cytokine, and IL-4, a TH2 cytokine, it will be determined whether these cytokines are essential for the cellular response mediated by CD4* T cells, and whether these cytokines are produced at the site of infection in the lung and the brain. Not previously considered by other investigators is the role of CD8* T cells in anti-Cryptococcal CMI. Studies are described here which will examine the Cryptococcus-induced host response in the lung, and determine whether CD8* T cell-mediated immunity can partially compensate for a deficit of CD4* T cells in resistance to this opportunistic pathogen.
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| Aguirre, K; Havell, E A; Gibson, G W et al. (1995) Role of tumor necrosis factor and gamma interferon in acquired resistance to Cryptococcus neoformans in the central nervous system of mice. Infect Immun 63:1725-31 |
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| Hill, J O (1992) CD4+ T cells cause multinucleated giant cells to form around Cryptococcus neoformans and confine the yeast within the primary site of infection in the respiratory tract. J Exp Med 175:1685-95 |
